Testing the excitation/inhibition imbalance hypothesis in a mouse model of the autism spectrum disorder: in vivo neurospectroscopy and molecular evidence for regional phenotypes

Abstract

BackgroundExcitation/inhibition (E/I) imbalance remains a widely discussed hypothesis in autism spectrum disorders (ASD). The presence of such an imbalance may potentially define a therapeutic target for the treatment of cognitive disabilities related to this pathology. Consequently, the study of monogenic disorders related to autism, such as neurofibromatosis type 1 (NF1), represents a promising approach to isolate mechanisms underlying ASD-related cognitive disabilities. However, the NF1 mouse model showed increased γ-aminobutyric acid (GABA) neurotransmission, whereas the human disease showed reduced cortical GABA levels. It is therefore important to clarify whether the E/I imbalance hypothesis holds true. We hypothesize that E/I may depend on distinct pre- and postsynaptic push-pull mechanisms that might be are region-dependent.MethodsIn current study, we assessed two critical components of E/I regulation: the concentration of neurotransmitters and levels of GABA(A) receptors. Measurements were performed across the hippocampi, striatum, and prefrontal cortices by combined in vivo magnetic resonance spectroscopy (MRS) and molecular approaches in this ASD-related animal model, the Nf1 +/− mouse.ResultsCortical and striatal GABA/glutamate ratios were increased. At the postsynaptic level, very high receptor GABA(A) receptor expression was found in hippocampus, disproportionately to the small reduction in GABA levels. Gabaergic tone (either by receptor levels change or GABA/glutamate ratios) seemed therefore to be enhanced in all regions, although by a different mechanism.ConclusionsOur data provides support for the hypothesis of E/I imbalance in NF1 while showing that pre- and postsynaptic changes are region-specific. All these findings are consistent with our previous physiological evidence of increased inhibitory tone. Such heterogeneity suggests that therapeutic approaches to address neurochemical imbalance in ASD may need to focus on targets where convergent physiological mechanisms can be found.

Symptom improvement in children with autism spectrum disorder following bumetanide administration is associated with decreased GABA/glutamate ratios

“…One study reported a correlation between GABA concentration in the visual cortex (VC) and the degree of perceptual suppression during binocular rivalry in adolescents with typical development, whereas the correlation was significantly lower in autistic patients 20 . Another study reported increased cortical and striatal GABA/glutamate ratios in a neurofibromatosis type 1 mouse model of autism 21 . Hence, the main aim of the current study using MRS is to determine whether bumetanide could regulate GABA/glutamate ratio in the brain and reduce the severity of the autistic symptoms in young children with ASD.…”

Connectome and microcircuit models implicate atypical subcortico-cortical interactions in autism pathophysiology

“…Histological studies have suggested several potential cellular substrates associated to connectome miswiring of autism including altered cortical lamination [76][77][78][79] and columnar layout 80,81 , together with atypical neuronal migration that can result in cortical blurring 77,82 and changes in spine density of cortical projection neurons 83,84 . Such cellular changes likely impact on the functional organization of cortical microcircuits in autism, also suggested by molecular studies in animals 4,[22][23][24][25]85,86 . These findings collectively support the imbalance in excitation and inhibition of cortical areas in autism 4,9,16,22,87,88 , which have been related to anomalies in cortical neurotransmitter systems [89][90][91][92] and atypical subcortico-cortical interactions with subcortical structures such as thalamus modulating this balance 7,11,24,74,75,93 .…”

Understanding autism spectrum disorder and social functioning in children with neurofibromatosis type 1: protocol for a cross-sectional multimodal study

“…Magnetic resonance spectroscopy (MRS) is an in vivo tool capable of non-invasively measuring brain metabolites. Only the MCRI site will acquire two GABA-edited magnetic resonance spectra using the localised spectroscopy sequence MEGA-PRESS, developed by CMRR, to evaluate the animal model-derived hypothesis that alterations in GABA and glutamate systems underlie cognitive and social impairments in NF1 53–55. MEGA-PRESS allows separation of GABA signals from stronger overlying signals of other metabolites 56.…”